The present invention relates to .beta.-N-substituted aminothiol esters represented by the general formula (I): ##STR3## wherein R.sup.1 is an alkyl group or an aryl group and R.sup.2 is an aralkyl group, a process for preparing the same, and azetidinone derivative represented by the general formula (VI): ##STR4## wherein R.sup.2 is an aralkyl group.
.beta.-N-Substituted aminothiol ester (I) of the present invention can be introduced into carbapenem .beta.-lactam antibiotics such as thienamycin. The carbapenem .beta.-lactam antibiotics show an excellent antibacterial activity against almost all bacteria including Pseudomonas aerugihosa, the antibacterial activity being much higher than the conventional drugs and with an excellent stability against .beta.-lactamase. Accordingly, the carbapenem .beta.-lactam antibiotics are greatly expected as the .beta.-lactam antibiotics of fourth generation.
Hitherto, the carbapenum .beta.-lactam antibiotics have been prepared by chemical synthesis in industry since its productivity in fermentation is quite low. In this point, the carbapenem .beta.-lactam antibiotics are quite different from the conventional penicillins or cephalosporin antibiotics.
Various carbapenem .beta.-lactam antibiotics have hitherto been in clinical stage. It is known by a person skilled in the art that these antibiotics are mainly prepared from an intermediate compound, i.e. .beta.-lactam represented by the general formula (II): ##STR5## wherein R.sup.3 and R.sup.4 are a protective group.
As a process for preparing the .beta.-lactam represented by the above formula (II), there have been known (1) a process in which a monocyclic .beta.-lactam ring having a side chain at 4-position is formed by asymmetric synthesis with an optically active amino acid or an enzyme and then a side chain is introduced at 3-position, (2) a process in which asymmetric carbon atoms corresponding to 3-position, 4-position and 1'-position are selectively formed by a special means and then the .beta.-lactam ring is formed, and (3) a process in which a monocyclic .beta.-lactam having a side chain at 3-position is formed from L-threonine or optically active penicillins and then a side chain is introduced at .varies.b-position [Masayuki Shibuya, "Yukigoseikagaku Kyokaishi, 41, 62(1983)].
However, the above process (1) is hard to be applied to an industrial process since it is rather difficult to introduce the side chain at 3-position and thus it is unsuitable for production in a large scale. Also the process (2), though the process has been industrially employed, has disadvantages such as a large number of preparing steps and involving the optical resolution. Further, the process (3), though the desired product can be obtained in an optically active form in the process, has also a disadvantage of so many producing steps. Recently, a process with a small number of synthesizing steps has been reported using optically active 3-hydroxybutyric acid [J. Am. Chem. Soc., 106, 4819 (1984); Chem. Lett., 1927 (1984); Chem. Lett., 651 (1985); Tet. Lett., 26, 937 (1985); Tet. Lett., 26, 1523 (1985)]. However, the process is still unsatisfactory in view point of a stereo-selectivity and a yield. As a result of earnest study of the present inventors in order to solve the above-mentioned problems, it has been found that .beta.-N-substituted aminothiol ester represented by the above-mentioned general formula (I) can be an excellent intermediate for producing .beta.-lactam compound represented by the above-mentioned general formula (II).
On the other hand, among compounds prepared starting from optically active 3-hydroxybutyric acid, one of the intermediate with broad appication is a compound represented by the formula (VII): ##STR6##
However, by the conventional method for the synthesis, the desired compound represented by the formula (VII) is produced as a by-product and the undesired stereoisomer represented by the formula (VIII): ##STR7## is produced with a high selectlvity. Therefore, for introducing into the carbapenem .beta.-lactam antibiotics such as thienamycin, a much complicated process of epimerization at 3-position is required [J. Am. Chem. Soc., 106, 4816 (1984); Chem. Lett., 1927 (1984); Chem. Lett., 651 (1985)]. Further, a process for preparing the above compounds (VII) and (VIII) comprises aldol condensation between the compound represented by the general formulas (IX): ##STR8## wherein R is methyl group or an alkyl group and the compound represented by the formula (X): ##STR9## Also it is noted that, in the above reaction, trimethylsilyl group is indispensable as a protective group of nitrogen atom and the reaction does not proceed with the protective groups other than trimethylsilyl group.
The present inventors have found that the azetidinone derivatives represented by the general formula (VI) is produced with a high selectivity from the optically active hydroxybutyric acid via the compound (I). The intermediate of the .beta.-lactam compound represented by the general formula (II) can be derived from the azetidinone derivatives represented by the general formula (VI) without a complicated process of epimerization at 3-position.